Catatonia is a widespread and serious syndrome characterized by mutism, stupor, refusal to eat or drink, posturing, and hypokinesis, and affects a broad range of psychiatric and other patients in the US and worldwide. Untreated or poorly managed catatonic patients suffer from a wide range of ailments including bed sores, deep venous thrombi, pulmonary emboli, urinary retention, infection, and aspiration pneumonia, which can lead to severe medical impairment and death. Existing treatments for catatonia including lorazepam (a benzodiazepine) often require high doses for an effective response, some patients are unresponsive, and chronic catatonia is poorly controlled. Discovery of a new treatment for catatonia would have a considerable commercial and scientific value. Our approach is to target an orphan drug receptor present in the cerebellum that is preferentially activated by lorazepam. We propose to carry out a Structure-Activity Relationship (SAR) program of synthesis and biological evaluation of specifically designed lorazepam derivatives. From this project we specifically aim to discover one or more benzodiazepine analogs showing the desired in vitro orphan drug receptor potency and selectivity. In Phase Two compounds with a promising in vitro profile will be examined in vivo in knockout mice to confirm their mode of action. The best lead compounds will be further optimized and then evaluated in an animal model for catatonia. The long- term goal of this project is to discover a new, improved pharmaceutical agent for treatment of catatonia that can be licensed and developed for ultimate market approval.